DESCRIPTION: Renewed support is sought for this long-standing postdoctoral research training grant in burn and trauma research based at the MGH in Boston and at affiliated institutions, including Harvard Medical School (HMS), the Shriners Burns Institute (SBI), and the Massachusetts Institute of Technology (MIT). The program director, Dr. Ronald G. Tompkins, received his M.D. degree from Tulane University Medical School in 1976 and his Sc.D. degree in chemical engineering from MIT in 1983; his surgical residency training was completed at MGH and HMS between 1976 and 1985, and he has continued on the staff of the MGH surgical services since 1985. Dr. Tompkins now holds the following positions: Chief, Trauma and Burns Service, MGH (1990 to present); Chief of Staff, SBI (1990 to present); Visiting Surgeon, Department of Surgery, MGH (1994 to present); and John Francis Burke Professor of Surgery, Department of Surgery, MGH (1996 to present). Dr. Tompkins directs the MGH Burn Trauma Center and serves on the Council of Biomedical Engineering at MGH and the Subcommittee of Professors at HMS. Dr. Tompkins' research interests in tissue engineering and artificial organs development and in metabolism and physiological transport in injury are supported by competitive outside funding. Dr. Tompkins lists more than 200 publications, and he has supervised dozens of postdoctoral fellows and graduate students. The co-director of this program, Dr. Martin L. Yarmush, received his Ph.D. degree in immunochemistry from Rockefeller University in 1979 and his M.D. degree from Yale University School of Medicine in 1984; Dr. Yarmush received postdoctoral training in immunology at NIH and completed the Ph.D. degree requirements in chemical engineering, excluding thesis work, at MIT in 1983. Dr. Yarmush now holds the following positions: Bioengineer, MGH (1995 to present); Helen Andrus Benedict Professor of Surgery and Bioengineering, HMS (1995 to present); and Director, Center for Engineering in Medicine (CEM), MGH (1995 to present). Dr. Yarmush has published over 130 research papers and supervised over 40 postdoctoral fellows. The former director of this training program, Dr. John F. Burke, will serve as principal investigator emeritus for this program. He received his M.D. degree from HMS in 1951, and he now holds the following positions: Visiting Surgeon, MGH (1968 to present); Helen Andrus Benedict Professor of Surgery, HMS (1976 to present); Visiting Professor, MIT (1977 to present); Chairman, Board of Directors, New England Life Flight (1987 to present); and Visiting Fellow, Bailiol College, Oxford (1991 to present). The program is administered by a Research Training Executive Committee (RTEC) comprising the program director and co-director and three participating faculty members; the current membership of this committee includes Drs. Tompkins and Yarmush, along with Drs. Toner, Fischman, and Young (see below). This committee is charged with: the oversight of program operations; defining a basic curriculum for each individual trainee; the planning and implementation of trainee recruitment; reviewing applications for the traineeships; assigning trainee advisors as needed; oversight of the research seminar series; the review of trainee research progress; and oversight of interactions between this training program and the Biomedical Engineering Research and Education for Physician Fellows (BERE) and CEM training programs. The participating faculty includes Drs. Tompkins, Yarmush, and Burke, along with eight other members, including: Alan Fischman, M.D., Ph.D., Associate Professor of Radiology, HMS; Director, Positron Emission Tomography (PET) Center, MGH; and Director of Nuclear Medicine, SBI and MGH. Charles A. Hales, M.D., Professor of Medicine, HMS; Associate Professor of Medicine, Harvard-MIT Division of Health Sciences and Technology (DHST); and Director of Research Laboratories at the MGH. Jeffrey R. Morgan, Ph.D., Assistant Professor of Biology, HMS; Senior Research Scientist, SBI; and Assistant Biologist, MGH. Wiley W. Souba, M.D., Sc.D., Professor of Surgery, HMS; Chief, Division of Surgical Oncology, MGH; and Director, Nutrition Support Unit, MGH. Gregory Stephanopoulos, Ph.D., Professor of Chemical Engineering, MIT; and Associate Director, Biotechnology Process Engineering Center, MIT. Mehmet Toner, Ph.D., Associate Professor of Surgery and Bioengineering, HMS; and Associate Bioengineer, Surgical Services, MGH. And W. Allan Walker, M.D., Conrad Taff Professor of Nutrition, HMS; Professor of Pediatrics, HMS; Professor of Nutrition, Harvard School of Public Health; and Chief, Combined Program in Pediatric Gastroenterology and Nutrition, HMS. The program will initially immerse the trainees in a focused group of didactic courses offered by Harvard and MIT. These classes are considered an essential component of the research training, and this approach has been developed and implemented during the past two years of the ongoing training program. Trainees are currently expected to take some combination of the following courses offered through the CEM: a Laboratory in Molecular and Cellular Sciences (Dr. Morgan); Fundamentals of Biomedical Engineering (Dr. Toner); Biostatistics (Dr. Elizabeth Myers); Case Studies in Biomedical Engineering I (Dr. Yarmush, focused on specialized engineering disciplines and applied examples); and Case Studies in Biomedical Engineering II (Dr. Tompkins, focused on clinical applications). In addition, all trainees will be expected to participate in the regular seminars, clinical conferences, the weekly research seminars, and the meetings of the Clinical Research Coordinating Committee for information exchange and presentation of research findings. Each trainee will be under the direct supervision of a participating faculty member who is responsible to the program director and to the RTEC to ensure the quality and progress of the research training. The participating faculty members are also engaged in NIH training grants in radiological sciences, nuclear magnetic resonance, and digestive diseases, and additional fellowships are available from institutional funds through the Surgical Service at MGH and the Shriners Hospital for Children (SHC) Fellowship program. A unifying hypothesis which underlies this trauma research training proposal is that severe burn injury induces a profound dyshomeostasis of nitrogen metabolism and of energy economy in the host in ways that are refractory to current therapies, thus compromising wound healing and recovery. It is postulated that these changes lead to a functional redistribution of nitrogen utilization and substrate metabolism among the wounded tissues and major body organs, to a quantitative reordering of the usual pathways of carbon and nitrogen flow among regions of the body, and to a depletion of required substrates and cofactors in key organs, such as the liver. Clinically related research training opportunities are focused in the following four areas that concern the impact of nutritional, hormonal, and pathophysiological factors on key aspects of substrate metabolism in living human subjects: (1) Energy and nitrogen relationships in burn and trauma (Drs. Souba and Young); (2) Tissue-specific metabolic responses to injury (Drs. Tompkins and Fischman); (3) Molecular mechanisms of burn induced insulin resistance (Drs. Tompkins, Avruch, and Fischman); and (4) Molecular basis of hepatic hypermetabolism in burns (Drs. Yarmush, Stephanopoulos, Tompkins, Toner, and Young). In addition, bioengineering-related research opportunities are offered in the following areas: (1) The development of a bioartificial liver (Drs. Tompkins, Yarmush, and Toner); (2) Development of skin replacement materials (Drs. Burke, Morgan, and Tompkins); (3) Cellular mechanisms of thermal injury (Drs. Toner, Tompkins, and Yarmush); (4) Antibody-targeted photolysis (Drs. Yarmush and Tompkins); and (5) Gene therapy for smoke inhalation (Drs. Morgan and Hales). Trainees are recruited among postdoctoral applicants with M.D. or Ph.D. degrees in biological or physical sciences, with a preference for physicians who seek careers involving research in basic and engineering science. Recruitment efforts include advertisements in scientific journals, mailings to academic programs, introductions at professional meetings, and personal recommendations. Selection is based on the candidate's scholastic record, on the relevance of the candidate's anticipated research to burns and trauma, and on the candidate's long-range commitment to research. Over the past five years, an average of more than 50 candidates have applied to this program each year, and the numbers have risen steadily from 18 to 93 per year during this period. For the current year, approximately one-third of the candidates are foreign, and two-thirds are United States citizens or permanent residents and thus eligible for training grant support. During these past five years, relatively constant numbers of candidates have been offered positions (an average of 12 per year) and have accepted positions (an average of 10 per year); an average of 2 fellows have completed the program each year, and a total of 2 trainees have left the program prior to completion (one to accept a faculty position at the University of Minnesota, and the other to shift research laboratories with other support). Over the past ten years, 23 trainees have received support from this grant, and 4 of these fellows are still active trainees in the program. These 23 trainees come from 21 different institutions, nationwide (including only two from HMS and one from MIT). Among the 19 graduates of this program during the past ten years, 10 now hold professorships (8 are assistant professors, and 2 are associate professors) at major academic institutions, and only one of these appointments is with a Harvard affiliate; another graduate now holds a full-time research position in industry; one graduate is an Instructor in Surgery at another academic institution, and the remaining six graduates have gone on to further training in medical specialties (five) or in basic science (one). The laboratory facilities routinely available to the trainees include the Knight laboratories for surgery on large animals, the mass spectroscopy laboratories at SBI and also at MIT, the NMR facilities and resources at MGH, the facilities and resources for tissue imaging and macromolecular localization at MGH and SBI, the MGH cyclotron and PET camera laboratories, and the mucosal immunology laboratory (of the Combined Program in Pediatric Gastroenterology and Nutrition) at MGH. This burns and trauma training program is based on clinical facilities that include a 32- bed Intensive Care Unit in the Burn Center that admits approximately 400 acutely burned patients each year, as well as the MGH Level I Trauma Center that admits more than 2,000 patients each year.